The overarching long range goal of this program project is to carry out translational research leading to the identification of genetic variants that act to increase the expression of endophenotypes that lead over time to the development of CVD and Type 2 diabetes (T2D), a major CVD risk factor. The central organizing theme of our research toward this goal over the next five years posits that genes and environmental exposures to various acute and chronic stressors across the life cycle influence - via both main and interactive effects -brain neurotransmitter systems in ways that affect the expression of health behaviors, psychological traits and states and neuroendocrine/autonomic functions in ways that alter metabolic, hemostatic, inflammatory and cardiovascular functions that are the proximal contributors to the development of T2D and/or CVD and/or precipitation of acute clinical events. Project 1 will use three existing samples with extensive data on these CVD and T2D endophenotypes to identify promising gene variants - using both candidate genes and GWAS-derived SNPs associated with T2D and CVD ~ that can be evaluated in Projects 2 and 3 for association with the same or similar predisease endophenotypes and CVD and/or T2D prevalence/incidence in two large cohorts. Project 2 will attempt to replicate the gene associations with the same or similar T2D and/or CVD endophenotypes found in Project 1 and test those variants for association with CVD and T2D in a large healthy nationally representative cohort, the Add Health sample (N=15,608). Project 3 will test these genetic variants for association with CVD & T2D and clinical events in a large cohort (N =8,000 -10,000) of Duke CAD patients who have undergone coronary angiography. RELEVANCE: The knowledge gained can be used to guide the development of the new field of prospective medicine, in which individuals at high risk of developing CVD and/or T2D can be identified earlier in the pathogenic process - before tissue damage has occurred - and targeted for preventive interventions to slow or prevent the development of disease and/or improve prognosis once disease is present. (End of Abstract)